Therapeutic ion exchange resin mixture



Patented Mar. 30, 1954 THERAPEUTIC ION EXCHANGE RESIN MIXTURE Kennetlr G. Kohlstaedt, Indianapolis, Ind., as-

signor'to Eli Lilly and Company, Indianapolis, Ind., a'corporation of Indiana No Drawing. Application November 3, 1950, Serial No. 194,033

This is a continuation-in-part of United States patent application Serial No. 156,508, filed April 17, 1950, now abandoned.

This invention relates to novel compositions useful in the treatment of edema associated with congestive heart failure, and like disorders.

In certain edematous conditions it has long been the practice to establish a negative sodium balance in the afilicted patient to decrease the concentration of sodium in extracellular space, thus producing a lower blood volume and minimizing the tendency toward edema or distressing ascites. Also, as is well known, the establishment of a low sodium concentration is desirable in cases of hypertension, to reduce arterial blood pressure.

A negative sodium balance and maintenance of a low sodium ion concentration in the body fluids has in the past been obtained either by administering diuretics to prevent renal resorption of sodium, or by the continued ingestion of a diet low in sodium. Both of these methods are disadvantageous. The former method requires frequent injections of a diuretic, which not only are painful but which if long continued may result in severe kidney damage. The latter method requires a strict dietary regime which is unpleasant to the patient and is well-nigh impossible of accomplishment unless the meals permitted by the diet are specially prepared. Accordingly, simpler methods of obtaining a negative sodium balance and maintaining a low sodium uptake are desirable.

From the standpoint of convenience of administration, one of the simplest methods of establishing a negative sodium balance would be to provide a composition capable of being taken orally by the patient, which composition would 4 Claims. (o1. 167-55) have the ability to combine with the sodium which which is ingested with a normal diet, and largely prevent its retention by the body system.

Such a composition, to be usable over long periods of time, must meet a number of requirements. The composition must havea high 03,-! pacity for combining with or fixing sodium ions and a low capacity for fixing the other metal ions which are essential to the well-being of the patient. It must be capable of administration in readily ingestible form. It must be insoluble, or nonabsorbable by the gastrointestinal tract. It must be without unpleasant odor or taste, or have such a mild odor or taste that any unpleasantness may readily be masked by suitable compounding. The composition must be nontoxic, and upon ingestion must produce no gastri'c'distress and no irritation or other untoward effect on the gastric mucosa.

In a search for a composition meeting the ,above requirements, it has recently been proirritating to the intestinal mucosa and causegastric pains. Moreover, they adsorb or fix all metal ions indiscriminately, so that after a relatively short time the treated subject suffers from the depletion of calcium, potassium and other metals essential to health.

I have discovered novel compositions which are highly effective in producing and maintaining a low sodium ion concentration in the body despite a normal dietary sodium intake. My compositions comprise a mixture of particular types of ion-exchange resins of uncombined and of salt forms. My invention includes within its scope compositions comprising essentially a mixture of a carboxylic resin in uncombined or acid form, and a carboxylic resin in potassium salt form. Also included within the scope of my invention as preferred embodiments thereof are compositions comprising a mixture of a carboX- ylic resin in acid and/or ammonium salt form, a carboxylic resin in potassium salt form, and an anion exchange resin in uncombined or basic form. For convenience, mixtures comprising the carboxylic resin in potassium salt, and acid salt form will hereafter be referred to as binary compositions, and those inclusive of the anion resin will be termed ternary compositions.

Binary compositions suitable for therapeutic administration range in ther make-up from about one part of the potassium salt form of the resin and four parts of the acid form ofthe resin, to about one part of the potassium salt form and one part of the acid form of the resin.

For most purposes, a composition comprising one part of the potassium salt form, and two parts of the acid form of the resin is desirable. In the preferred ternary compositions there is incorporated in the above binary mixtures an amount which can range up to about one part (with reference to the amount of potassium salt form) of an anion exchange resin.

The binary mixtures of this invention are useful in short term treatment and in those cases wherethe patient has a good renal function and has sufiered no impairment in his ability to produce ammonia in the kidneys. In such cases any tendency toward acidosis resulting from ingestion of the resin mixture is offset by the ability of the kidney to produce ammonia. for combination with and elimination of chloride and other anions. The acid-producing qualities of the carboxylic acid resin can be offset to an extent by employment of the resin in its ammonium salt form. This is but a partial solution of the problem, however, as the anion (commonly the chloride ion) remaining after removal of the sodium cation is in its effect in the body an acidic ion, and requires removal. Means of removing the chloride ion (or other acidic anions) is provided in the ternary compositions of this invention by the inclusion therein of the anion exchange resin. The addition of the anion exchange resin not only prevents the development of an acidosis in the patient under treatment, but also appears to increase the efficiency of the carboxylic resin so that a more effective removal of sodium is obtained. The amount of anion exchange resin employed in the compositions is in part controlled bythe degree of renal impairment in the patient and by the relative amount of the acid form of the carbo xylic resin in the composition, greater amounts of anion exchange resin being preferred in compositions containing a large proportion of acid carboxylic resin, and/or appreciable renal impairment.

My novel compositions are prepared by a mixing together of the ion exchange resins in the proportions required for the particular composition desired. The acid, and the potassium forms of the carboxylic resin can be of the same or different resins. The resins being powders need no further processing to make them cap-able of oral ingestion, a simple mixing being sufiicient. However, because the resins are most readily ingested when in the form of aqueous suspensions, it is desirable to have the resins in finely powdered form and to incorporate in the mixture a small amount of wetting agent to assist in obtaining a ready dispersion of the powder in water.

Various carboxylic ion-exchange resins can be employed in the preparation of compositions of the above character. Thusfor example, the car boxylic acid resins sold by Robin and Haas under the names Amberlite XE-64 and IRS-50 are satisfactory. Other carboxylic resins, for example that sold by Permutit Company under the name Permutit XAC, are also suitable. Generally, the resins are available inthe acid form only. To provide the potassium salt or the ammonium salt form used in compounding the compositions of this invention, any of the usual and known procedures for converting acid resins into their salt forms can be used, as for example, treating the acid resin with a solution of potassium hydroxide, anddrying the resin salt thus produced.

A variety of anion exchange resins can be employed in the preparation of the compositions of this invention. Thus for example; both polyamine and quaternary ammonium typeresins can be employed. Resins found to be quite acceptable for the purposes of this invention are those of the character described in United States Patent No. 2,402,384, issued June 18, 1948. A resin of the type disclosed in the patent is that sold by Rohm and Haas under the'name Amberlite XE-58.

It is surprising that the compositions of this invention are so effective in adsorbing the sodium ions present in the gastrointestinal tract, for past 4 experience with carboxylic resins has demon strated their inability to fix appreciable amounts of sodium ions in the acid and alkaline ranges existing within the gastrointestinal tract. It is further surprising, but an observed fact, that the mixtures of resins employed herein apparently exhibit within the body a peculiar tendency to adsorb sodium ions in preference to other ions so that continued ingestion of the compositions of this invention does not deplete the body of other essential metal ions as might be expected. Inlong-term clinical trials of the compositions of this invention, careful analyses conducted upon blood samples has, failed to detect any depletion of essential metal ions.

Illustrative compositions within the scope of this invention are as follows, the proportions being expressed in parts by weight:

Composition A Parts Amberlite XE-64 (acid form) 2 Amberlite XE-fiel (potassium salt form) 1 A composition prepared in accordance with the above formula, when administered in amount of about 30 to 50 g. per day, maintains a low sodium concentration in the body fluids in a patient ingesting a normal diet, '(kllli; is, a diet which will supply about 3 g. of sodium per day.

Composition 13 Parts Amberlite Kid-64 (acid form) i Amber-lite XE-fii (potassium salt form) 1 A composition of the above character is especially suitable for treating patients having an impaired renal function. The composition When administered in an amount of about 25 to 35 g. per day will maintain a low sodium concentration in the body fluids and will leave the concentrations of the other essential metals substantially unchanged.

Composition C Parts Amberlite- XE-Ei l (acid form) 1 Amberlite XE-64 (potassium salt form) 1 The above composition administered in amounts of about 30 to 40 g. per day provides excellent control; of sodium concentration in patients having an unimpaired renal function. The relatively large amount of potassium present in the above composition not only serves in itself to displace sodium, but in addition, acts as a diuretic, and in so acting serves to provide renal clearance for additional sodium. A composition containing a relatively large amount of potassium as does the above illustrative example, is especially suitable for providing a rapid decrease in the sodium content of the body fluids.

Composition D Parts Amberl1te XE-54 (acid form) 5 Amberlite XE-(S i (potassium salt form) 2.5 "Amberlite XE-58 1 Theabove composition administered in aqueous suspension in the amount of about 40 to 7 (1" g. per day (depending upon the amount of dietary sodium) provides an excellent control of sodium concentration, and can be administered to pa tients having extensive renal damage over long periods of time without depletion of essential ions or production of any observable metabolic imgla A onion.

ing agent in the above mixture.

The dispersibility of the above composition in water is improved by incorporation of a dispers- For example Tween 80 is intimately mixed with the anion exchange resin in the amount of about 0.5 percent by weight, prior to the mixing of the resin powders.

The above illustrative compositions, which are in the form of dry powders, are made readily ingestible their suspension in water. In place of aqueous simple suspensions which settle out rapidly, more stable and permanent suspensions are prepared by mixing the powder with an aqueous solution of a thickening agent, for example, methyl cellulose or acacia. The suspension can be further stabilized by the addition of a substantially nontoxic, nonionic, emulsifying agent. Paiatability of the above compositions can be increased by the addition of suitable flavoring agents.

The method of converting the acid form of a resin into the potassium salt form is illustrated by the following conversion of acid Amberlite XE-64 into its potassium salt form.

To 5 /2 pounds of the acid form of Amberlite XE-E is added a solution of 1850 g. of potassium hydroxide in 16 liters of water. The mixture is allowed to stand for about 24 hours, with occasional stirring. The mixture is diluted with an equal volume of distilled water, is filtered, and the residue consisting of the resin in potassium salt form is washed thoroughly with distilled water. The moist precipitate of potassium resin is dried at 60 C. in vacuo.

I claim:

1. A therapeutically effective ion-exchange resin composition adapted for the removal of sodium ions from the gastrointestinal tract, said composition being substantially free from sodium,

and comprising essentially about one part of the potassium salt form of a oarboxylic ion-exchange resin, and from about one to about four parts of a carboxylic ion-exchange resin in acid form.

2. A therapeutically efiective ion-exchange resin composition adapted for the removal of sodiuin ions from the gastrointestinal tract, said composition being substantially free from sodium, and comprising essentially about one part of the potassium salt form of a carboxylic ion-exchange resin and about two parts of a carboxylic ion-exchange resin in acid form.

3. A therapeutically efiective ion-exchange resin composition adapted for the removal of sodium ions from the gastrointestinal tract, said composition being substantially free from sodium, and comprising essentially about one part of a carboxylic ion-exchange resin in potassium salt form, about one to about four parts of a carboxylic ion-exchange resin in acid form, and an amount up to about one part of an anion exchange resin.

4. A therapeutically efiective ion-exchange resin composition adapted for the removal of sodium ions from the gastrointestinal tract, said composition being substantially free from sodium, and comprising about two and one half parts of a carboxylic ion-exchange resin in potassium salt form, about five parts of a carboxylic ion-exchange resin in acid form, and about one part of an anion exchange resin.

KENNETH G. KOHLSTAEDT.

References Cited in the his of this patent UNITED STATES PATENTS Number Name Date 2,409,861 Hunter Oct. 22, 1946 2,531,035 Martin Jan. 1, 1952 OTHER REFERENCES volume 6, April 28, November 1949, pages 1493 to 1411.

Amberlite, IRC-50, April 1948 (9 pages), Rohm and Haas Company, Philadelphia, Pa.

Kunin, Analytical Chemistry, January 1949, pages 87 to 96.

Kunin, Industrial & Engineering Chemistry, June 1949, pages 1265 to 1272. 

1. A THERAPUETICALLY EFFECTIVE ION-EXCHANGE RESIN COMPOSITION ADAPTED FOR THE REMOVAL OF SODIUM IONS FROM THE GASTROINTESTINAL TRACT, SAID COMPOSITION BEING SUBSTANTIALLY FREE FROM SODIUM, AND COMPRISING ESSENTIALLY ABOUT ONE PART OF THE POTASSIUM SALT FORM OF A CARBOXYLIC ION-EXCHANGE RESIN, AND FROM ABOUT ONE TO ABOUT FOUR PARTS OF A CARBOXYLIC ION-EXCHANGE RESIN IN ACID FORM. 